Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.

Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis / Galata G.; Garcia-Montero A.C.; Kristensen T.; Dawoud A.A.Z.; Munoz-Gonzalez J.I.; Meggendorfer M.; Guglielmelli P.; Hoade Y.; Alvarez-Twose I.; Gieger C.; Strauch K.; Ferrucci L.; Tanaka T.; Bandinelli S.; Schnurr T.M.; Haferlach T.; Broesby-Olsen S.; Vestergaard H.; Moller M.B.; Bindslev-Jensen C.; Vannucchi A.M.; Orfao A.; Radia D.; Reiter A.; Chase A.J.; Cross N.C.P.; Tapper W.J.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - ELETTRONICO. - 108:(2021), pp. 284-294. [10.1016/j.ajhg.2020.12.007]

Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis

Guglielmelli P.;Ferrucci L.;Vannucchi A. M.;Cross N. C. P.;
2021

Abstract

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.
2021
108
284
294
Galata G.; Garcia-Montero A.C.; Kristensen T.; Dawoud A.A.Z.; Munoz-Gonzalez J.I.; Meggendorfer M.; Guglielmelli P.; Hoade Y.; Alvarez-Twose I.; Gieger C.; Strauch K.; Ferrucci L.; Tanaka T.; Bandinelli S.; Schnurr T.M.; Haferlach T.; Broesby-Olsen S.; Vestergaard H.; Moller M.B.; Bindslev-Jensen C.; Vannucchi A.M.; Orfao A.; Radia D.; Reiter A.; Chase A.J.; Cross N.C.P.; Tapper W.J.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1257173
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